Title:DNA Cleaving “Tandem-Array” Metallopeptides Activated With KHSO<sub>5</sub>: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds
VOLUME: 10 ISSUE: 1
Author(s):Mark A. Lewis, Katie M. Williams, Ya-Yin Fang, Franklin A. Schultz and Eric C. Long
Affiliation:Department of Chemistry & Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI), 402 North Blackford Street, Indianapolis, IN 46202-3274.
Keywords:DNA cleavage, metallopeptide, Gly-Gly-His, metal binding peptide.
Abstract:Amino terminal peptides of the general form Gly-Gly-His have been used to introduce single sites of metal
binding and redox activity into a wide range of biomolecules to create bioactive compounds and conjugates capable of
substrate oxidation. We report here that Gly-Gly-His-like peptides linked in a tandem fashion can also be generated leading
to multi-metal binding arrays. While metal binding by the native Gly-Gly-His motif (typically to Cu2+, Ni2+, or Co2+)
requires a terminal peptide amine ligand, previous work has demonstrated that an ornithine (Orn) residue can be substituted
for the terminal Gly residue to allow solid-phase peptide synthesis to continue via the side chain N-δ. This strategy
thus frees the Orn residue N-α for metal binding and permits placement of a Gly-Gly-His-like metal binding domain at
any location within a linear, synthetic peptide chain. As we show here, this strategy also permits the assembly of tandem
arrays of metal binding units in linear peptides of the form: NH2-Gly-Gly-His-[(δ)-Orn-Gly-His]n-(δ)-Orn-Gly-His-
CONH2 (where n = 0, 1, and 2). Metal binding titrations of these tandem arrays monitored by UV-vis and ESI-MS indicated
that they bind Cu2+, Ni2+, or Co2+ at each available metal binding site. Further, it was found that these systems retained
their ability to modify DNA oxidatively and to an extent greater than their parent M(II)•Gly-Gly-His. These findings
suggest that the tandem array metallopeptides described here may function with increased efficiency as “next generation”
appendages in the design of bioactive compounds and conjugates.
